An Efficient, Multicomponent, One-pot Synthesis of Tetra Substituted Pyrans in Water

Article abstract of DOI:10.1002/jhet.2125

A new and environmentally benign multi-component synthesis of tetra substituted 4H-pyran derivatives is developed via the one-pot reaction of an aromatic aldehyde, malononitrile, and 1,3-diketone in the presence of NaOH with water as the solvent at RT. Th

Full text of DOI:10.1002/jhet.2125

Month 2014
An Efficient, Multicomponent, One-pot Synthesis of Tetra Substituted
Pyrans in Water
R. Pagadala, S. Maddila, and S. B. Jonnalagadda*
School of Chemistry & Physics, University of KwaZulu-Natal, Westville Campus, Chiltern Hills, Durban 4000, South Africa
*
E-mail: jonnalagaddas@ukzn.ac.za
Additional Supporting Information may be found in the online version of this article.
Received June 27, 2013
DOI 10.1002/jhet.2125
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
R
O
CHO
R
O
O
Et
CN
CN
CN
NaOH
O
Et
O
HOH, rt
O
NH2
95-99%
A new and environmentally benign multi-component synthesis of tetra substituted 4H-pyran derivatives is
developed via the one-pot reaction of an aromatic aldehyde, malononitrile, and 1,3-diketone in the presence
of NaOH with water as the solvent at RT. The reaction is efficient and affords excellent yields of the products.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
obtained in the presence of ethanol/methanol [21]. There is
still wide scope to develop new efficient, cost-effective and
eco-sustainable methods for the synthesis of tetra substituted
pyrans. To our knowledge, there are no similar reports in the
literature on the synthesis of tetra-substituted 4H-pyrans.
The heterocyclic synthesis is crucial, because heterocyclic
derivatives occupy a central role in our increasingly techno-
logical society. Heterocyclic compounds have retained their
prominence as an integral part of new drug discovery.
Multicomponent reactions have proved to be powerful and
efficient bond-forming tools in modern heterocyclic and
medicinal chemistry [1]. The pharmaceutical industries.
which continually search for new chemicals and drugs need
to be cognizant of green solutions for their syntheses [2].
Water [3] and ionic liquids [4] have attracted attention as
eco-friendly solvents for organic synthesis.
RESULTS AND DISCUSSIONS
Our studies were aimed at developing new selective
and eco-friendly approaches for the preparation of
heterocyclic compounds. In this communication, we re-
port a simple and environmentally compatible method
to synthesize 4H-pyrans under moderate conditions in
good yields with water as the solvent. As a part of this,
we embarked on the synthesis of 4H-pyrans under
alkaline conditions with water as the solvent. The
optimization of the reaction conditions, including the
quantity of base, reaction medium, and nature of base
were investigated, and the results are summarized in
Table 1. The described method accommodated a wide
spectrum of three-component reactions with good to
excellent yield of the target compounds.
The synthesis of poly-functionalized 4H-pyrans is
important as they represent key building blocks of
several natural and synthetic heterocyclic compounds
[
5,6]. 4H-Pyrans are attractive to researchers because
of their pharmacological and biological activities such as
antitumor, antibacterial, antiviral, spasmolytic, antifungal,
anti-inflammatory, and anti-anaphylactic properties [7–13].
Thus, in view of their wide utility, the synthesis of such
compounds is an appealing challenge.
Of the many methods available for the synthesis of 4H-
pyrans, the most widely used is the one-pot, three-component
synthesis, catalyzed by metal oxides and mixed metal oxides
To generalize our methodology, several pyrans 4a–i
were synthesized. Reactions were carried out simply by
reacting various substituted benzaldehydes 2a (1.0 equiv.),
[
14–16], Cu(II) oxymetasilicate [17], organic bases [18],
Baker’s yeast [19], and ionic liquids [20]. However, many
of the synthetic methods for 4H-pyrans reported so far suffer
from one or more drawbacks. Most require prolonged reaction
times, expensive catalysts, harsh reaction conditions, and
tedious work-ups. Many of those provide moderate yields.
Dong et al. have stated that some pyridines can only be
malononitrile 3 (1.0 equiv.), and 1, 3-diketone 1
(1.0 equiv.) in the presence of aqueous NaOH at RT
(Scheme 1). All the synthesized compounds were charac-
1
13
terized and confirmed by IR, H-NMR, C-NMR, and
mass spectra. Compounds 4a, 4h, and 4i were further
15
identified by N-NMR (GHSQC) to confirm the presence
©
2014 HeteroCorporation

R. Pagadala, S. Maddila, and S. B. Jonnalagadda
Vol 000
of the –NH group in their structure. The reaction mecha-
synthesis of substituted 4H-pyrans, because the hydrogen
bonds formed facilitate the dual activation of both electrophile
and nucleophiles. Hence, water has enhanced characteristics
relative to organic solvents for the synthesis of the pyrans
reported here.
2
nism may tentatively be visualized to occur via a tandem
sequence of the reactions depicted in the reaction schemes
in Mechanism 1.
N
NC
O
O
H
CONCLUSION
Et
CN
NH
O
R
H
In conclusion, for the first time, we report a novel and
one-pot tandem method involving a three-component
system for synthesizing a series of tetra-substituted 4H-
pyrans by using NaOH as catalyst in water. Our method
has many advantages over the existing procedures, such
as elimination of organic solvents, high yields, simple
work-up, cost-effectiveness, non-toxic catalyst, and no
column-chromatography requirement in most cases. In
this procedure, no organic solvent is used except as an
eluent in TLC.
O
O
O
Et
-
OH
CN
N
O
CHO
R
NC
H
NC
O
O
CN NaOH
CN
base
O
O
R
R
O
Et
Et
X
OH
NH
NH
OH
NC
NC
C
NC
O
H
NH
H
-
H2O
O
R
R
EXPERIMENTAL
O
O
O
O
O
O
Et
Et
General remarks. All chemicals used were reagent grade
and were used as received without further purification.
H-NMR and C-NMR spectra were recorded at 25°C at 400
Et
1
13
and 100 MHz (Bruker Avance, Switzerland) instrument
respectively, using TMS as internal standard. Chemical shifts
are given in parts per million (ppm). The FT-IR spectroscopy
of samples were carried out on a Perkin Elmer (Maryland, US)
R
O
t
CN
O
À1
Precisely 100 FT-IR spectrometer in the 400–4000 cm
region. Liquid chromatography–mass spectrometry (LCMS)
mass spectra were recorded on a Mass Spectrometry and
Proteomics Center low resolution mass spectrometer operating
at 70 eV. Elemental analyses were carried out using a Perkin-
Elmer CHNS Elemental Analyzer model 2400. Melting points
are uncorrected and were recorded on a hot stage melting
point apparatus Ernst Leitz Wetzlar, Germany. Reactions were
monitored, and the purity of products was checked out on
TLC on aluminum-backed plates coated with Kieselgel
Mechanism 1. Plausible reaction mechanism for the synthesis of tetra-
substituted 4H-pyrans.
Interestingly, all the reactions are clean, and the products
were obtained with simple workup, filtration, and washing
with water. As the purity of the product was high, no
further recrystallization was required except for 4b and
4
e, which were further purified by column chromatogra-
6
0 F254 silica gel, visualizing the spots under UV light and
phy. The yields of the products are presented in Table 2.
This study describes an efficient approach for the synthesis
of substituted pyrans by using NaOH in aqueous conditions.
Water plays an important role in the three-component oriented
iodine chamber.
General experimental procedure for the synthesis of 4H-
Pyran.
Water (5 mL) was added to the solution containing
freshly distilled benzaldehyde (1.0 mmol), malononitrile (1.0
Table 1
Optimization of reaction conditions of the multicomponent reactions.
a
Entry
Product No.
Base
Amount (equiv.)
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
6a
NaOH
NaOH
TEA
2.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
H
H
H
CH
DMF
2
2
2
O
O
O
8.0
4.0
4.0
8.0
8.0
8.0
6.0
6.0
65.0
99.0
20.0
0.0
0.0
50.0
0.0
K
2
K
2
K
2
CO
CO
CO
3
3
3
2
Cl
2
H
2
O
TEA
TEA
CH
DMF
2
Cl
2
0.0
a
Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
An Efficient, Multicomponent, One-Pot Synthesis of Tetra Substituted Pyrans in Water
Scheme 1. Synthesis of tetra-substituted 4H-pyran (4a–i) derivatives via a three-component coupling of ethylacetoacetate (1), substituted aromatic
aldehydes (2a–i), and malononitrile (3).
O
ROH
Et
CN
OR
O
Ref [21]
R = Me, E
N
R
CHO
R
HOH
X
O
O
CN
CN
NaOH
O
Et
Et
CN
OH
O
O
N
(
1)
(2a-i)
(3)
Our results
R
HOH
O
Et
CN
NH
O
(4a-i)
O
Table 2
Multicomponent reaction for the synthesis of tetra- substituted 4H-pyrans (4a–i).
a
Entry
Product no.
R
1
Time (h)
Yield (%)
MP (°C)/(lit)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
4.0
4.0
3.5
4.0
4.0
4.0
4.0
3.5
3.5
99.0
95.0
98.0
97.0
96.0
99.0
98.0
98.0
96.0
186–188 (192) [15]
130–132 (136) [15]
172–173 (172–174) [22]
166–168 (170) [15]
178–180 (182) [15]
179–181 (175–177) [23]
163–165
4-OCH
4-Br
4-Cl
4-NO
4-OH
4-N(CH
2-Cl
2-Br
3
2
3 2
)
168–170
176–178
a
Isolated yields.
mmol) and ethylacetoacetate (1.0 mmol). After 5 min of stirring
5 ml of NaOH (4.0 equiv.) solution was added, stirring at RT.
6-Amino-5-cyano-2-methyl-4-(4-(dimethylamino)phenyl)-
4H-pyran-3-carboxylic acid ethyl ester (4g). Off-white
1
1
The reaction mixture was stirred at RT for 4 h. After, the
starting material was consumed (monitored by TLC [EtOAc/
hexane = 4:6)] and then poured saturated aqueous NaCl (15 mL)
solution into the reaction mixture. The reaction mixture was
stirred for 30 min and set on one side to separate solid.
Solid deposit was collected by the filtration and was
washed with water to give a pure product 4a (99% yield)
solid; H-NMR (400 MHz, DMSO-d ) δ =0.94 (3H, t, J=7.0Hz),
6
2.37 (3H, s), 3.0 (6H, s), 3.9 (2H, q, J= 4.5 Hz), 4.84 (1H, s), 6.83
13
(2H, d, J= 9.1 Hz), 6.91 (2H, s), 7.81 (2H, d, J=9.1Hz); C-NMR
(100 MHz, DMSO-d ): δ 13.5, 18.0, 35.1, 56.2, 60.0, 68.5, 105.4,
6
119.1, 126.6, 127.8, 128.9, 144.4, 157.6, 158.8, 165.6; IR (KBr,
À1
+
cm ) 3402, 3328, 2197, 1679; LCMS of [C H N O +H ]
1
8 21 3 3
(m/z): 328 (100%); Anal. calcd: C 66.04, H 6.47, N 12.84%.
as a white solid.
Found: C 66.08, H 6.45, N 12.87%.
The spectral (IR, 1H-NMR, and MS) data of the unknown
6-Amino-5-cyano-2-methyl-4-(2-chlorophenyl)-4H-pyran-3-
1
products are given.
carboxylic acid ethyl ester (4h).
Off-white solid; H-NMR
6
-Amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylic
(400 MHz, DMSO-d ) δ =0.93 (3H, t, J= 7.0 Hz), 2.33 (3H, s),
6
1
acid ethyl ester (4a). White solid; H-NMR (400 MHz, DMSO-
3.89 (2H, q, J= 4.5 Hz), 4.87 (1H, s), 6.92 (2H, s), 7.17–7.28 (4H,
13
d ) δ = 1.05(3H, t, J = 7.0 Hz), 2.33 (3H, s), 3.97–4.00 (2H, m),
m); C-NMR (100 MHz, DMSO-d ): δ 13.5, 18.0, 35.2, 56.0,
6
6
13
4
.31 (1H, s), 6.92 (2H, s), 7.15–7.35 (5H, m); C-NMR
60.0, 105.9, 119.1, 127.7, 128.3, 129.2, 129.7, 131.9, 142.0, 157.7,
À1
(
100MHz, DMSO-d ): δ 13.6, 18.0, 57.1, 60.1, 107.1, 119.6,
158.4, 165.1; IR (KBr, cm ) 3425, 3330, 2194, 1684; LCMS of
6
À1
+
1
3
3
5
26.7, 127.1, 128.3, 144.8, 156.5, 158.4, 165.4; IR (KBr, cm
395, 3327, 2189, 1682; HRMS of [C H N O + Na] (m/z):
07.1066 (100%); calcd mass: 307.1059; Anal. calcd: C 67.59, H
.67, N 9.85%. Found: C 67.57, H 5.68, N 9.88%.
)
[C H ClN O +H ] (m/z): 319 (100%); Anal. calcd: C 60.29, H
16
15
2 3
1
6 16 2 3
4.74, N 8.79%. Found: C 60.35, H 4.72, N 8.84%.
6-Amino-5-cyano-2-methyl-4-(2-bromophenyl)-4H-pyran-3-
1
carboxylic acid ethyl ester (4i).
Off-white solid; H-NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Pagadala, S. Maddila, and S. B. Jonnalagadda
Vol 000
(
400 MHz, DMSO-d ) δ = 0.94 (3H, t, J = 7.0 Hz), 2.33 (3H, s), 3.89
[7] Zhang, S.; Fernandez, F.; Hazeldine, S.; Deschamps, J.; Zhen,
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6
(
2H, q, J = 4.0 Hz), 4.87 (1H, s), 6.91 (2H, s), 7.12–7.55 (4H, m);
1
3
6
C-NMR (100MHz, DMSO-d ): δ 13.5, 18.0, 35.1, 56.2, 60.0,
1
1
06.1, 119.0, 122.6, 128.3, 128.6, 129.7, 132.4, 143.8, 157.7,
[9] Souza, L. C.; Santos, A. F.; Goulart Sant’ Ana, A. E.; Oliveira
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58.3, 165.1; IR (KBr, cm ) 3429, 3334, 2190, 1685; LCMS of
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16
15
2 3
4
.16, N 7.71%. Found: C 52.87, H 4.21, N 7.78%.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet